The Long Journey into BRCA1/2 Genes Goes On: The Emerging Landscape in BRCA-Mediated Tumors

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Molecular Cancer Biology".

Deadline for manuscript submissions: closed (31 December 2020) | Viewed by 34158

Special Issue Editors


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Guest Editor
Department of Surgical, Oncological and Oral Sciences, University of Palermo, 90127 Palermo, Italy
Interests: predictive and prognostic factors in solid tumors; identification of therapeutic target; pancreatic cancer; hereditary breast and ovarian cancer; meta-analysis; liquid biopsy; precision oncology
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Guest Editor
Department of Biomedicine, Neuroscience and Advanced Diagnostics, University of Palermo, 90127 Palermo, Italy
Interests: soft tissue sarcomas; gastrointestinal stromal tumors; gynecological and genitourinary tumors; cancer genetics; hereditary breast and ovarian cancers; prognostic and predictive biomarkers; molecular mechanisms of targeted therapy and immunotherapy resistance
Special Issues, Collections and Topics in MDPI journals

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Guest Editor
Section of Medical Oncology, University Hospital Policlinico “Paolo Giaccone” - Palermo. 90127 Palermo, Italy
Interests: Molecular biology and translational research of rare tumors; heredo-familial tumors; Gene expression; Molecular pathway network in solid tumors; Cancer tumor microenvironment; Tumor immunology; Predictive and prognostic biomarkers in oncology
Special Issues, Collections and Topics in MDPI journals

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Guest Editor
Department of Biomedicine, Neuroscience and Advanced Diagnostics, University of Palermo, 90127 Palermo, Italy
Interests: cancer genetics and genomics; familial/hereditary solid tumors; breast/ovarian cancer genes; homologous recombination; liquid biopsy; precision oncology

Special Issue Information

Dear Colleague,

The critical role of BRCA1 and BRCA2 genes was discovered for the first time in 1994 and 1995 in families with a high prevalence of breast and ovarian cancers. Pathogenic variants in these genes remain, to date, the primary inherited cause of breast and ovarian tumors, with an 85% lifetime risk for breast and a 20–40% risk for ovarian cancer. However, research in the past two decades has brought great progress and change in the field of breast and ovarian cancer, screening, prevention, and treatment. The diffusion of high-throughput next-generation sequencing technologies has provided a deep insight into the molecular biology of these tumors and many other genes and proteins within the homologous recombination pathway have been evaluated. The development of poly(ADP-ribose) polymerase inhibitors (PARPi) has been a major advance in the treatment of ovarian tumors and several clinical and translational trials are ongoing to validate prognostic and predictive utility of germline and/or somatic pathogenic variants in BRCA1/2 or other genes associated with HRD as biomarkers in breast and ovarian cancer. More recent evidence has shown the presence of BRCA1/2 and pathogenic variants of other genes also in pancreatic and prostate cancer; this event increases the risk and contributes to the prevalence of these cancers not just in high-risk families but in the general population as well.

That is how the long journey into BRCA genes goes on, and the emerging landscape of genetic testing and management of BRCA-mediated tumor phenotypes (and beyond) continues to evolve.

Prof. Antonio Russo
Dr. Lorena Incorvaia
Dr. Daniele Fanale
Prof. Viviana Bazan
Guest Editors

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Keywords

  • hereditary breast and ovarian cancer
  • genetic predisposition to cancer
  • BRCA1 and BRCA2
  • homologous recombination deficiency (HRD)
  • BRCA-related pancreatic cancer
  • BRCA-related prostate cancer
  • multigene panel
  • NGS

Published Papers (8 papers)

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Research

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21 pages, 1195 KiB  
Article
Application of Multilayer Evidence for Annotation of C-Terminal BRCA2 Variants
by Henriett Butz, János Papp, Anikó Bozsik, Lilla Krokker, Tímea Pócza, Edit Oláh and Attila Patócs
Cancers 2021, 13(4), 881; https://doi.org/10.3390/cancers13040881 - 20 Feb 2021
Cited by 3 | Viewed by 2449
Abstract
The clinical relevance of the BRCA2 C-terminal stop codon variants is controversial. The pathogenic role of the germline BRCA2 c.9976A>T and c.10095delinsGAATTATATCT variants in hereditary breast and ovarian cancer (HBOC) patients was evaluated. An association with clinicopathological parameters was performed in 2491 independent [...] Read more.
The clinical relevance of the BRCA2 C-terminal stop codon variants is controversial. The pathogenic role of the germline BRCA2 c.9976A>T and c.10095delinsGAATTATATCT variants in hereditary breast and ovarian cancer (HBOC) patients was evaluated. An association with clinicopathological parameters was performed in 2491 independent probands diagnosed with HBOC and in 122,209 cancer patients reported earlier. Loss-of-heterozygosity (LOH) in tumor samples and allelic imbalance in RNA extracted from peripheral blood cells were investigated. Neither c.10095delinsGAATTATATCT or c.9976A>T variants showed significant association with clinicopathological parameters or elevated risk for HBOC-associated tumors. Lung cancer was more prevalent in families carrying the c.9976A>T variant compared to pathogenic BRCA1 or BRCA2 carrier families. An increased prevalence of pancreatic cancer was found in families where c.9976A>T occurred together with other pathogenic BRCA1 variants. An increased risk for familial pancreatic, lung and upper aero-digestive tract cancers was confirmed in the validation set. Regarding BRCA2 C-terminal variants, no linkage with other pathogenic BRCA2 variants, no LOH in tumor tissue and no allelic imbalance in RNA level were confirmed. The c.9976A>T variant may be considered as a potential risk for lung cancer, and a potential modifying factor in pancreatic cancer when it occurs along with the pathogenic BRCA1 variant, although this observation should be validated in a larger sample cohort. Full article
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16 pages, 1317 KiB  
Article
Detection of Germline Mutations in a Cohort of 139 Patients with Bilateral Breast Cancer by Multi-Gene Panel Testing: Impact of Pathogenic Variants in Other Genes beyond BRCA1/2
by Daniele Fanale, Lorena Incorvaia, Clarissa Filorizzo, Marco Bono, Alessia Fiorino, Valentina Calò, Chiara Brando, Lidia Rita Corsini, Nadia Barraco, Giuseppe Badalamenti, Antonio Russo and Viviana Bazan
Cancers 2020, 12(9), 2415; https://doi.org/10.3390/cancers12092415 - 25 Aug 2020
Cited by 37 | Viewed by 4298
Abstract
Patients with unilateral breast cancer (UBC) have an increased risk of developing bilateral breast cancer (BBC). The annual risk of contralateral BC is about 0.5%, but increases by up to 3% in BRCA1 or BRCA2 pathogenic variant (PV) carriers. Our study was aimed [...] Read more.
Patients with unilateral breast cancer (UBC) have an increased risk of developing bilateral breast cancer (BBC). The annual risk of contralateral BC is about 0.5%, but increases by up to 3% in BRCA1 or BRCA2 pathogenic variant (PV) carriers. Our study was aimed to evaluate whether all BBC patients should be offered multi-gene panel testing, regardless their cancer family history and age at diagnosis. We retrospectively collected all clinical information of 139 BBC patients genetically tested for germline PVs in different cancer susceptibility genes by NGS-based multi-gene panel testing. Our investigation revealed that 52 (37.4%) out of 139 BBC patients harbored germline PVs in high- and intermediate-penetrance breast cancer (BC) susceptibility genes including BRCA1, BRCA2, PTEN, PALB2, CHEK2, ATM, RAD51C. Nineteen out of 53 positively tested patients harbored a PV in a known BC susceptibility gene (no-BRCA). Interestingly, in the absence of an analysis performed via multi-gene panel, a significant proportion (14.4%) of PVs would have been lost. Therefore, offering a NGS-based multi-gene panel testing to all BBC patients may significantly increase the detection rates of germline PVs in other cancer susceptibility genes beyond BRCA1/2, avoiding underestimation of the number of individuals affected by a hereditary tumor syndrome. Full article
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19 pages, 1495 KiB  
Article
Spectrum of Germline BRCA1 and BRCA2 Variants Identified in 2351 Ovarian and Breast Cancer Patients Referring to a Reference Cancer Hospital of Rome
by Concetta Santonocito, Roberta Rizza, Ida Paris, Laura De Marchis, Carmela Paolillo, Giordana Tiberi, Giovanni Scambia and Ettore Capoluongo
Cancers 2020, 12(5), 1286; https://doi.org/10.3390/cancers12051286 - 19 May 2020
Cited by 20 | Viewed by 5203
Abstract
Pathogenic variants (PVs) carriers in BRCA1 or BRCA2 are associated with an elevated lifetime risk of developing breast cancer (BC) and/or ovarian cancer (OC). The prevalence of BRCA1 and BRCA2 germline alterations is extremely variable among different ethnic groups. Particularly, the rate of [...] Read more.
Pathogenic variants (PVs) carriers in BRCA1 or BRCA2 are associated with an elevated lifetime risk of developing breast cancer (BC) and/or ovarian cancer (OC). The prevalence of BRCA1 and BRCA2 germline alterations is extremely variable among different ethnic groups. Particularly, the rate of variants in Italian BC and/or OC families is rather controversial and ranges from 8% to 37%, according to different reports. By In Vitro Diagnostic (IVD) next generation sequencing (NGS)-based pipelines, we routinely screened thousands of patients with either sporadic or cancer family history. By NGS, we identified new PVs and some variants of uncertain significance (VUS) which were also evaluated in silico using dedicated tools. We report in detail data regarding BRCA1/2 variants identified in 517 out of 2351 BC and OC patients. The aim of this study was to report the incidence and spectrum of BRCA1/2 variants observed in BC and/or OC patients, tested in at Policlinico Gemelli Foundation Hospital, the origin of which is mainly from Central and Southern Italy. This study provides an overview of the variant frequency in these geographic areas of Italy and provides data that could be used in the clinical management of patients. Full article
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11 pages, 765 KiB  
Article
BRCA Detection Rate in an Italian Cohort of Luminal Early-Onset and Triple-Negative Breast Cancer Patients without Family History: When Biology Overcomes Genealogy
by Angela Toss, Eleonora Molinaro, Marta Venturelli, Federica Domati, Luigi Marcheselli, Simonetta Piana, Elena Barbieri, Giovanni Grandi, Claudia Piombino, Isabella Marchi, Elena Tenedini, Enrico Tagliafico, Giovanni Tazzioli and Laura Cortesi
Cancers 2020, 12(5), 1252; https://doi.org/10.3390/cancers12051252 - 15 May 2020
Cited by 18 | Viewed by 3817
Abstract
NCCN Guidelines recommend BRCA genetic testing in individuals with a probability >5% of being a carrier. Nonetheless, the cost-effectiveness of testing individuals with no tumor family history is still debated, especially when BRCA testing is offered by the national health service. Our analysis [...] Read more.
NCCN Guidelines recommend BRCA genetic testing in individuals with a probability >5% of being a carrier. Nonetheless, the cost-effectiveness of testing individuals with no tumor family history is still debated, especially when BRCA testing is offered by the national health service. Our analysis evaluated the rate of BRCA pathogenic or likely-pathogenic variants in 159 triple-negative breast cancer (TNBC) patients diagnosed ≤60 years, and 109 luminal-like breast cancer (BC) patients diagnosed ≤35 without breast and/or ovarian family histories. In TNBC patients, BRCA mutation prevalence was 22.6% (21.4% BRCA1). Mutation prevalence was 64.2% ≤30 years, 31.8% in patients aged 31–40, 16.1% for those aged 41–50 and 7.9% in 51–60 s. A total of 40% of patients with estrogen receptors (ER) 1–9% were BRCA1 carriers. BRCA detection rate in early-onset BCs was 6.4% (4.6% BRCA2). Mutation prevalence was 0% between 0–25 years, 9% between 26–30 years and 6% between 31–35 years. In conclusion, BRCA testing is recommended in TNBC patients diagnosed ≤60 years, regardless of family cancer history or histotype, and by using immunohistochemical staining <10% for both ER and/PR. In luminal-like early-onset BC, a lower BRCA detection rate was observed, suggesting a role for other predisposing genes along with BRCA genetic testing. Full article
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20 pages, 1591 KiB  
Article
Hereditary Breast and Ovarian Cancer in Families from Southern Italy (Sicily)—Prevalence and Geographic Distribution of Pathogenic Variants in BRCA1/2 Genes
by Lorena Incorvaia, Daniele Fanale, Giuseppe Badalamenti, Marco Bono, Valentina Calò, Daniela Cancelliere, Marta Castiglia, Alessia Fiorino, Alessia Pivetti, Nadia Barraco, Sofia Cutaia, Antonio Russo and Viviana Bazan
Cancers 2020, 12(5), 1158; https://doi.org/10.3390/cancers12051158 - 5 May 2020
Cited by 27 | Viewed by 3969
Abstract
Recent advances in the detection of germline pathogenic variants (PVs) in BRCA1/2 genes have allowed a deeper understanding of the BRCA-related cancer risk. Several studies showed a significant heterogeneity in the prevalence of PVs across different populations. Because little is known about [...] Read more.
Recent advances in the detection of germline pathogenic variants (PVs) in BRCA1/2 genes have allowed a deeper understanding of the BRCA-related cancer risk. Several studies showed a significant heterogeneity in the prevalence of PVs across different populations. Because little is known about this in the Sicilian population, our study was aimed at investigating the prevalence and geographic distribution of inherited BRCA1/2 PVs in families from this specific geographical area of Southern Italy. We retrospectively collected and analyzed all clinical information of 1346 hereditary breast and/or ovarian cancer patients genetically tested for germline BRCA1/2 PVs at University Hospital Policlinico “P. Giaccone” of Palermo from January 1999 to October 2019. Thirty PVs were more frequently observed in the Sicilian population but only some of these showed a specific territorial prevalence, unlike other Italian and European regions. This difference could be attributed to the genetic heterogeneity of the Sicilian people and its historical background. Therefore hereditary breast and ovarian cancers could be predominantly due to BRCA1/2 PVs different from those usually detected in other geographical areas of Italy and Europe. Our investigation led us to hypothesize that a higher prevalence of some germline BRCA PVs in Sicily could be a population-specific genetic feature of BRCA-positive carriers. Full article
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Review

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17 pages, 940 KiB  
Review
The Role of BRCA1/2-Mutated Tumor Microenvironment in Breast Cancer
by Svetlana Miklikova, Lenka Trnkova, Jana Plava, Martin Bohac, Marcela Kuniakova and Marina Cihova
Cancers 2021, 13(3), 575; https://doi.org/10.3390/cancers13030575 - 2 Feb 2021
Cited by 9 | Viewed by 4620
Abstract
Taking into account the factors of high incidence rate, prevalence and mortality, breast cancer represents a crucial social and economic burden. Most cases of breast cancer develop as a consequence of somatic mutations accumulating in mammary epithelial cells throughout lifetime and approximately 5–10% [...] Read more.
Taking into account the factors of high incidence rate, prevalence and mortality, breast cancer represents a crucial social and economic burden. Most cases of breast cancer develop as a consequence of somatic mutations accumulating in mammary epithelial cells throughout lifetime and approximately 5–10% can be ascribed to monogenic predispositions. Even though the role of genetic predispositions in breast cancer is well described in the context of genetics, very little is known about the role of the microenvironment carrying the same aberrant cells impaired by the germline mutation in the breast cancer development and progression. Based on the clinical observations, carcinomas carrying mutations in hereditary tumor-suppressor genes involved in maintaining genome integrity such as BRCA1/2 have worse prognosis and aggressive behavior. One of the mechanisms clarifying the aggressive nature of BRCA-associated tumors implies alterations within the surrounding adipose tissue itself. The objective of this review is to look at the role of BRCA1/2 mutations in the context of breast tumor microenvironment and plausible mechanisms by which it contributes to the aggressive behavior of the tumor cells. Full article
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16 pages, 2863 KiB  
Review
PARP Inhibitors in the Treatment of Early Breast Cancer: The Step Beyond?
by Anthony Gonçalves, Alexandre Bertucci and François Bertucci
Cancers 2020, 12(6), 1378; https://doi.org/10.3390/cancers12061378 - 27 May 2020
Cited by 27 | Viewed by 4820
Abstract
Exquisitely exploiting defects in homologous recombination process, poly(ADP-ribose) polymerase (PARP) inhibitors have recently emerged as a promising class of therapeutics in human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer with germline breast cancer 1 (BRCA1) or breast cancer 2 (BRCA2) mutations [...] Read more.
Exquisitely exploiting defects in homologous recombination process, poly(ADP-ribose) polymerase (PARP) inhibitors have recently emerged as a promising class of therapeutics in human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer with germline breast cancer 1 (BRCA1) or breast cancer 2 (BRCA2) mutations (gBRCA1/2m). In this setting, PARP inhibitors, either as single agent or in combination with platinum-based chemotherapy, significantly increased progression-free survival, as compared to conventional chemotherapy. Accordingly, further therapeutic advances are expected at an earlier stage of the disease. In the neoadjuvant setting, veliparib failed to increase the pathological complete response rate when added to a carboplatin-based regimen, in unselected triple-negative breast cancer patients. Similarly, when administered before anthracycline-cyclophosphamide, the neoadjuvant olaparib-paclitaxel combination was not superior to carboplatin–paclitaxel, in patients with HER2-negative breast cancer and BRCA1/2 mutation, or homologous recombination defect. Yet, neoadjuvant talazoparib, administered as a single-agent in patients with HER2-negative breast cancer and germline BRCA1/2 mutation, achieved an impressive pathological complete response rate of nearly 50%. In the adjuvant setting, the results from the OlympiA phase III study, evaluating adjuvant olaparib in HER2-negative early breast cancer and germline BRCA1/2 mutations, are eagerly awaited. Ongoing trials should clarify whether PARP inhibitors might improve outcome when administered in the adjuvant or neoadjuvant setting in early breast cancer patients with BRCA1/2 mutation or homologous recombination defect. Full article
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Other

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12 pages, 273 KiB  
Guidelines
Bringing Onco-Innovation to Europe’s Healthcare Systems: The Potential of Biomarker Testing, Real World Evidence, Tumour Agnostic Therapies to Empower Personalised Medicine
by Denis Horgan, Gennaro Ciliberto, Pierfranco Conte, Giuseppe Curigliano, Luis Seijo, Luis M. Montuenga, Marina Garassino, Frederique Penault-Llorca, Fabrizia Galli, Isabelle Ray-Coquard, Denis Querleu, Peter Riegman, Keith Kerr, Hein Van Poppel, Anders Bjartell, Giovanni Codacci-Pisanelli, Jasmina Koeva-Balabanova, Angelo Paradiso, Zorana Maravic, Vassiliki Fotaki, Nuria Malats, Chiara Bernini, Simonetta Buglioni, Alastair Kent, Elisabetta Munzone, Ivica Belina, Jan Van Meerbeeck, Michael Duffy, Beata Jagielska and Ettore Capoluongoadd Show full author list remove Hide full author list
Cancers 2021, 13(3), 583; https://doi.org/10.3390/cancers13030583 - 2 Feb 2021
Cited by 15 | Viewed by 3778
Abstract
Rapid and continuing advances in biomarker testing are not being matched by uptake in health systems, and this is hampering both patient care and innovation. It also risks costing health systems the opportunity to make their services more efficient and, over time, more [...] Read more.
Rapid and continuing advances in biomarker testing are not being matched by uptake in health systems, and this is hampering both patient care and innovation. It also risks costing health systems the opportunity to make their services more efficient and, over time, more economical. The potential that genomics has brought to biomarker testing in diagnosis, prediction and research is being realised, pre-eminently in many cancers, but also in an ever-wider range of conditions—notably BRCA1/2 testing in ovarian, breast, pancreatic and prostate cancers. Nevertheless, the implementation of genetic testing in clinical routine setting is still challenging. Development is impeded by country-related heterogeneity, data deficiencies, and lack of policy alignment on standards, approval—and the role of real-world evidence in the process—and reimbursement. The acute nature of the problem is compellingly illustrated by the particular challenges facing the development and use of tumour agnostic therapies, where the gaps in preparedness for taking advantage of this innovative approach to cancer therapy are sharply exposed. Europe should already have in place a guarantee of universal access to a minimum suite of biomarker tests and should be planning for an optimum testing scenario with a wider range of biomarker tests integrated into a more sophisticated health system articulated around personalised medicine. Improving healthcare and winning advantages for Europe’s industrial competitiveness and innovation require an appropriate policy framework—starting with an update to outdated recommendations. We show herein the main issues and proposals that emerged during the previous advisory boards organised by the European Alliance for Personalized Medicine which mainly focus on possible scenarios of harmonisation of both oncogenetic testing and management of cancer patients. Full article
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